The overall goal of Project IV is to eradicate actinic keratosis (AK) and dysplastic nevi (DN), reduce the incidence of non-melanoma skin cancers (NMSC) and melanoma, and to develop basic science and clinical research approaches that will serve as models for the chemoprevention of a wide range of human epithelial cancers. There is a 3-7 fold increased incidence of NMSC and melanoma in southeastern Arizona. Approximately 60% of squamous cell carcinomas (SCC) arise from pre-existing AKs and/or contiguous skin surfaces. AKs may represent a significant risk factor for melanoma as well. Epidemiologic studies found that DN are a strong risk factor for melanoma. Researchers agree that the probability of successfully altering the natural history of any cancer increases by targeting an earlier, rather than a later, time point in carcinogenesis. Our research group has attempted to dissect the UVB and UVA signal transduction pathways leading to NMSC and melanoma with the aim of identifying molecular targets for chemopreventive agent development that ultimately will lead to more effective primary and secondary prevention strategies. An essential part of this research approach is a requirement to validate that the molecular targets identified in the UVB- and UVA-induced NMSC and melanoma mouse carcinogenesis models in Projects I, II and Ill are also present in UVB- and UVA-induced human skin tumor progression, in year 1 of Project IV, we will perform a clinical study to cross validate the molecular targets for chemoprevention agent development between mouse and human models of UVB and UVA skin carcinogenesis. As the continuing central focus of this clinical research project, in years 1-5 participants with preclinical AKs, AKs, benign nevi and DN will be recruited for phase I, lla and lib randomized placebo-controlled cancer prevention clinical trials of topical agents (and oral Vitamin A in phase lib trials) as individual drugs or in combination regimens (depending on their activity and/or tolerance in preclinical studies, including: 1) perillyl alcohol, 2) apomine, 3) p38 MAP kinase inhibitor (prodrug of SB202190), 4) PI-3 kinase inhibitor (LY294002 or inositol hexaphosphate), 5) EGFR tyrosine kinase (TK) inhibitors [PD153035, AG1478, ZD1839 (lressa)], 6) perillyl alcohol prodrug, 7) JNK inhibitor (SP600125), and 8) DFMO prodrug. Agents selected must be shown to be: 1) active in at least one mouse UV carcinogenesis model or one transgenic mouse melanoma model; 2) locally and systemically nontoxic in murine models; and 3) able NCI-E 25 2 P01 CA027502-23A1 ALBERTS, D to penetrate and concentrate in full thickness skin from SKH-1 mice. A specialized Drug Development Core (Core D) will supply the most optimal drug or prodrug formulations and drug concentrations for each topical chemopreventive agent for Phase I clinical studies. We also propose to characterize and quantify histopathologic, karyometric, and immunohistochemical biomarkers (e.g. apoptosis by morphology and caspase 3, PCNA, p53, COX-2, c-Fos, CREB-P and other developmental molecular targets identified in Projects I-Ill) that occur in preclinical AKs and DN in response to phase Ila and lib treatment regimens. Finally, we will determine the predictive accuracy of optical coherence tomography (OCT) with respect to identification of abnormal histopathologic and karyometric areas of forearm skin epidermis in study participants with sun damaged skin and/or AKs.